Somatostatin (somatotropin release inhibiting factor; SRIF), a tetradecapeptide originally isolated from ovine hypothalamus on the basis of its ability to inhibit growth hormone release from anterior pituitary cells (Brazeau, P. et al., Science 179, 77-79, 1973) has been shown to be present in several other tissues (for a review see Reichlin, S., N. Engl. J. Med. 309, 1495-1501, 1983 and ibid, 1556-1563). Somatostatin appears to have widespread functions as a modulator of neuronal activity as well as of endocrine and exocrine secretion. Inhibitory effects of this peptide on the release of a variety of hormones such as growth hormone, prolactin, glucagon, insulin, gastrin and thyroid stimulating hormones have been described (for a review see Wass, J. A. H., in Endocrinology, ed. deGrott, L. J., vol 1, 152-166, 1989). Somatostatin is best regarded as belonging to a phylogenetically ancient, multigene family of peptides with two important bioactive products, namely SRIF-14 (SRIF) and SRIF-28, a congener of SRIF extended at the N-terminus.
The regulatory functions of SRIF are mediated by specific membrane receptors. Currently, only agonists are available to study the pharmacology of SRIF receptors. High-affinity saturable binding sites have been demonstrated in a number of tissues, e.g. pituitary gland, brain and pancreas. Within the last few years the cloning and isolation of five somatostatin receptor genes has been reported for various species (human, rat, mouse and bovine). Structural analysis of the encoded proteins revealed that the somatostatin receptor proteins (SST1-SST5) represent a distinct receptor subfamily (named the A5 subfamily) belonging to the superfamily of G protein-coupled receptors with seven putative membrane spanning regions.
Recent work on the development of nonpeptide structures substituting the peptide backbone of small cyclic peptides with a .beta.-D-glucose scaffold (Hirschmann, R. et al, J.Am. Chem.Soc. 115, 12550-12568, 1993) or xylofuranose scaffold (Papageorgiou, C. et al., Bioorg.Med.Chem.Lett. 2, 135-140, 1992) demonstrated low somatostatin receptor affinity. However, these structures are nonselective displaying higher affinities for both .beta.2-adrenergic receptors and tachykinin receptors. Thus, there have been no reports in the literature on the successful development of a selective, competitive somatostatin receptor ligand of nonpeptide origin.
The H3 receptor is known and of current interest for the development of new medicaments (see. e.g. Stark, H.; Schlicker, E.; Schunack, W. Drugs Fut. 1996, 21, 507-520; Leurs, R.; Timmerman, H.; Vollinga, R. C. Progress in Drug Research 1995, 45, 107-165). The histamine H3 receptor is a presynaptic autoreceptor located in both the central and the peripheral nervous system, the skin and in organs such as the lung, the intestine, probably the spleen and the gastrointestinal tract. Stimulation of the H3 receptor with an agonist leads to an inhibition of the biosynthesis and the release of histamine (autoreceptor), and also of other neurotransmitters (heteroreceptor), such as serotonine and acetylcholine. These findings indicate that the H3 receptor is a target for new therapeutics.